The present invention relates to a process for the preparation of 1, 2, 3, 4, 8, 9, 10, 10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole derivatives and intermediates thereof, the final products being useful in the treatment of central nervous system disorders, including obsessive-compulsive disorder, depression, anxiety, generalized anxiety disorder, schizophrenia, panic disorder, migraine, sleep disorders, such as sleep apnea, eating disorders, such as hyperphagia, obesity, epilepsy, and spinal cord injury.
Obesity is a medical disorder characterized by an excess of body fat or adipose tissue. Comorbidities associated with obesity are Type II diabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke, osteoarthritis, sleep apnea, gall bladder disease, gout, some cancers, some infertility, and early mortality. As the percentage of obese individuals continues to rise both in the U.S. and abroad, obesity is expected to be a major health risk in the 21st Century. The serotonin 5-hydroxytryptamine (5-HT) receptor is a G-protein coupled receptor which is expressed in neurons in many regions of the human central nervous system. [Wilkinson, L. O. and Dourish, C. T. in Serotonin Receptor Subtypes: Basic and Clinical Aspects (ed. Peroutka, S. J. ) 147-210 (Wiley-Liss, N.Y., 1991).] The 5HT2C receptor (formerly called the 5HT1C receptor) is a prominent subtype of the serotonin receptor found in the central nervous system of both rats and humans. It is expressed widely in both cortical and subcortical regions. [Julius, D. MacDermott, A. B., Axel, R. Jessell, T. M. Science 241:558-564 (1988).] Studies in several animal species and in humans have shown that the non-selective 5HT2C receptor agonist, meta-chlorophenylpiperazine (MCPP) decreases food intake. [Cowen, P. J., Clifford, E. M. , Williams, C., Walsh, A. E. S., Fairburn, C. G. Nature 376: 557 (1995).] Tecott, et al have demonstrated that transgenic mice lacking the 5HT2C receptor eat more and are heavier than Wild Type mice. [Tecott, L. H., Sun, L. M., Akana, S. F., Strack, A. M., Lowenstein, D. H., Dallman, M. F., Jullus, D. Nature 374: 542-546 (1995).] Compounds of this invention are 5HT2C receptor subtype selective agonists which are selective over other monoamine receptors, causes a reduction in food intake and result in a reduction in weight gain. Other therapeutic indications for 5HT2C agonists are obsessive compulsive disorder, depression, panic disorder, schizophrenia, sleep disorders, eating disorders, and epilepsy.
The non-selective 5-HT2C agonist, meta-chlorophenylpiperazine (m-CPP), has been shown to block conditioned avoidance responding (CAR) in the rat, an activity usually associated with antipsychotic activity in man [Martin, Gregory E.; Elgin, Jr., Robert J.; Mathiasen, Joanne R.; Davis, Coralie B.; Kesslick, James M.; Baldy, William J.; Shank, Richard P.; DiStefano, Deena L.; Fedde, Cynthia L.; Scott, Malcolm K. J. Med. Chem. 1989, 32, 1052-1056]. More recently, additional data suggests that 5-HT2C agonism may produce an antipsychotic-like effect in the CAR model [Browning, J. L.; Young, K. A.; Hicks, P. B. Presented at the 29th Annual Meeting of the Society for Neuroscience, Miami Beach, Fla., October 1999, Abstract 830.12].
U.S. Pat. No. 3,914,250 (Oct. 21, 1975) describes 1,4-diazepino[6,5,4-jk]carbazoles, having the structures below, as anticonvulsant agents. 
Pyrrolo[3,2,1-jk][1,4]benzodiazepines and 4,5-dihydropyrrolo[3,2,1-jk][1,4]-benzodiazepines have been described by Hester et aL (J. Med. Chem. 1970, 13, 827-835) to have central nervous system activity. 
The present invention provides processes for the preparation of 1, 2, 3, 4, 8, 9, 10, 10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6, 7,1-hi]indole derivatives of the general formula: 
wherein:
R is hydrogen, alkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl;
R1, R2, R4and R5 are each, independently, hydrogen, hydroxy, alkyl of 1-6 carbon atoms, cycloalkyl, alkoxy of 1-6 carbon atoms, halogen, fluorinated alkyl of 1-6 carbon atoms, xe2x80x94CN, xe2x80x94NHxe2x80x94SO2-alkyl of 1-6 carbon atoms, xe2x80x94SO2xe2x80x94NH-alkyl of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, fluorinated alkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, aryl, or aroyl;
R3 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl, alkoxy of 1-6 carbon atoms, fluorinated alkyl of 1-6 carbon atoms, xe2x80x94NHxe2x80x94SO2-alkyl of 1-6 carbon atoms, xe2x80x94SO2xe2x80x94NH-alkyl of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, fluorinated alkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, aryl, or aroyl;
or a pharmaceutically acceptable salt thereof.
The definitions above of fluorinated alkyl and fluorinated alkoxy groups indicate the specified alkyl or alkoxy groups having any amount of fluorine substitution including, but not limited to, groups such as xe2x80x94CHF2, xe2x80x94CF3, xe2x80x94C2F5, xe2x80x94OCF3, etc.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereoisomers. While shown without respect to stereochemistry in Formula I, the present invention includes such optical isomers and diastereoisomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
The term xe2x80x9calkylxe2x80x9d includes both straight- and branched-chain saturated aliphatic hydrocarbon groups. The term xe2x80x9caroylxe2x80x9d is defined as an aryl ketone, where aryl is defined as an aromatic system of 6-14 carbon atoms, which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system. Preferred aryl groups include phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl groups. Halogen is defined as F, Cl, Br, and I.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids. The processes herein will be understood to include an optional additional step of forming a salt form of the products via standard addition reactions with any pharmaceutically acceptable organic or inorganic acid.
Preferred compounds prepared by the processes of this invention are those in which R is hydrogen. Another preferred group of compounds of this invention are those in which R and R3 are hydrogen and R1, R2, R4 and R5 are as defined above. In another group of compounds herein, R, R3, R2, and R5 are hydrogen and R1 and R4 are as defined above. A further group comprises compounds wherein R, R1, R2, R3, and R4 are hydrogen and R5 is as defined above. In a final group R, R1, R2, R3, R4 and R5 are each hydrogen.
The 5HT2C receptor agonists of this invention are useful for the treatment or prevention in mammals, preferably in humans, of disorders involving the central nervous system such as obsessive-compulsive disorder, depression, atypical depression, bipolar disorders, anxiety, generalized anxiety disorder, schizophrenia, psychoses, personality disorders, organic mental disorders, behavioral disorders associated with dementia or age-related conditions, aggressivity, drug and alcohol addiction, social phobias, sexual dysfunction, panic disorder, migraine, steep disorders, such as sleep apnea, eating disorders, such as hyperphagia, bulimia or anorexia nervosa, obesity, epilepsy, and premenstrual tension.
This invention also includes methods of utilizing the compounds herein in treatments or preventitive regimens for treatment of central nervous system deficiencies associated with trauma, stroke, neurodegenerative diseases or toxic or infective CNS disorders including, but not limited to, encephalitis or menengitis; or cardiovascular disorders, including thrombosis; gastrointestinal disorders such as malfunction of gastrointestinal motility; and diabetes insipidus. These methods include the improvement or inhibition of further degradation of central nervous system activity during or following the malady or trauma in question. Included in these improvements are maintenance or improvement in motor and motility skills, control, coordination and strength.
A process of this invention comprises a method of preparing a compound of the formula: 
wherein R, R1, R2, R3, R4 and R5 are as defined above, the process comprising the steps of:
a) reacting an optionally substituted cyclopentaindole-5-carboxylic acid of the formula III with an amino acid ester of formula IV, wherein Rxe2x80x2 represents an alkyl group of from 1 to 10 carbon atoms, to produce an optionally substituted cyclopentaindole-5-carbonyl-amino acetic acid alkyl ester of formula V; 
b) treating the optionally substituted cyclopentaindole-5-carbonyl-amino acetic acid alkyl ester of formula V from step a) with a reducing agent to provide an optionally substituted cyclopenta[b]indole-5-carbonyl-amino-acetic acid alkyl ester of the formula VI: 
c) hydrolysing the reduced ester compound of formula VI in the presence of a base, followed by treatment with an acid, to form an optionally substituted diaza-benzo[cd]lcyclopenta[a]azulene-4,7-dione compound of formula VII: 
d) treating the optionally substituted diaza-benzo[cd]cyclopenta[a]azulene-4,7-dione compound of formula VII with a reducing agent to provide a compound of the formula VIII: 
The process described above further comprises an optional step of treating the compound of formula VIII with an alkylating agent or an acylating agent to provide a compound of the formula: 
wherein R is hydrogen, alkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; and R1, R2, R3, R4 and R5 are as defined above.
This process also comprises an optional step of treating a compound of Formula VII or Formula I with a pharmaceutically acceptable organic or inorganic acid to form a corresponding pharmaceutically acceptable addition salt form of the compound of Formulas VII or I.
Compounds of formula I are new compounds. In Scheme I and in the following description and examples the process steps are explained in detail. A 2-hydrazinobenzoic acid I is allowed to react with a ketone II under standard Fischer-indole conditions. The reaction is carried out in the presence of an acid, such as sulfuric acid or acetic acid, with or without a solvent, such as water or ethanol, at a temperature above ambient temperature, such as 30-150xc2x0 C.
The resulting indole-carboxylic acid III is coupled with an amino acid ester IV, such as L-alanine methyl ester, in the presence of peptide coupling reagents, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole hydrate (HOBt), and a base, such as diisopropylethylamine, in an inert organic solvent, such as dichloromethane. It will be understood that the amino acid ester IV may comprise any known in the art to be used in cyclization procedure as disclosed in Scheme 1. Among the most preferred are those wherein Rxe2x80x2 in formula IV are represent alkyl groups of from 1 to 10 carbon atoms, either straight, branched or cyclic. Among the most preferred are the shorter chain esters, such as the methyl, ethyl, isopropyl, n-propyl, n-butyl, and t-butyl esters.
The resulting indole-amide V can be reduced to indoline-amide VI using conventional reduction methods, for instance by catalytic hydrogenation in the presence of a metal catalyst, such as 5% Pd/C, or by a hydride source, such as triethylsilane or borane, in the presence of an acid, such as trifluoroacetic acid.
The indoline-amide VI can be cyclized to the bislactam VII by hydrolysis of the ester with a base, such as lithium hydroxide, and subsequent treatment with an acid, such as acetic acid. 
The bislactam VII can be reduced to the benzodiazepine VIII with a reducing agent, such as borane or lithium aluminum hydride, in the presence of an inert organic solvent, such as tetrahydrofuran.
Reaction of benzodiazepine VIII with an alkyl halide, such as methyl iodide, or an acyl halide, such as acetyl chloride, or an aroyl chloride, such as benzoyl chloride, gives IX.
The acylation steps of this invention are understood to include reactions of the appropriate compound with any acylating agent and reaction conditions known in the art. Useful in these steps are acylating agents include acid halides and esters or anhyrides of the appropriate aliphatic carboxylic acid. Useful acid halides include acetyl chloride, propionyl chloride, isobutyryl chloride, benzoyl chloride, etc. Acid anhydrides include acetic anhydride and benzoic anhydride. Similarly, alkylation steps herein are understood to include any relevant alkylating agents and conditions known in the art. These include, but are not limited to the use of alkyl halides, such as methyl iodide, or alkyl tosylates or aldehyde alkylating agents in the presence of an applicable reducing agent.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known pharmaceutically acceptable acids. The processes herein will be understood to include an optional additional step of forming a salt form of the products via standard addition reactions with any pharmaceutically acceptable organic or inorganic acid.
A method of resolving the (R,R) enantiomer from racemic mixtures of these compounds comprises the steps of:
a) dissolving about 1 equivalent of the racemic compound mixture of a product of this invention in a solubilizing amount of an alcohol resolving agent at a temperature of from about 50xc2x0 C. to the reflux temperature for the alcohol, preferably between about 50xc2x0 C. and 70xc2x0 C., under an inert atmosphere, to create a resolving solution;
b) treating the resolving solution of step a) with from about 0.1 to about 0.35 equivalents of dibenzoyl-L-tartaric acid, preferably from about 0. 15 equivalents to about 0.3 equivalents, more preferably from about 0.23 to about 0.27 equivalents, most preferably about 0.25 equivalents to precipitate the desired (R,R) enantiomer from the resolving solution as the corresponding tartaric acid salt form; and
c) separating the desired enantiomer from the resolving solution through conventional means, such as filtration.
It will be understood that this process may be followed by additional steps of filtration and purification to enhance the purity and yield of the desired enantiomer product in question.
In step b) it is preferred that the temperature of the resolving solution be maintained at a temperature at or above about 50xc2x0 C., preferably nearer to the reflux temperature of the alcohol in question. The alcohol component of step a) may be comprise a single alcohol or a combination of two or more alcohols selected from those known in the art into which the compound in question can be dissolved. Among the preferred alcohols are the commercially available and relatively low boiling alcohols comprising 10 carbon atoms or less including methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, cyclohexanol, etc.
It will also be understood that the (S,S) enantiomer of the racemic mixture mentioned above could then be purified and collected from the remaining resolving solution described above after collection of the (R,R) tartaric acid salt.
An analogous method for resolving the (S,S) enantiomer from the racemic mixtures of compounds of this invention, the method comprising the steps a) through c) listed above, with dibenzoyl-D-tartaric acid being used in place of dibenzoyl-L-tartaric acid in step b). Comparably, the (R,R) enantiomer can be collected and purified by conventional means from the remaining solution after the tartaric acid salt form of the (S,S) enantiomer is precipitated and removed in this analogous method.